The Function of SWAP-70 in Mast Cells

描述（由申请人提供）：肥大细胞在哺乳动物免疫系统中发挥着多种重要作用。当Fc-epsilonRI受体聚集时，肥大细胞可以脱粒并释放组胺和其他生物活性化合物。虽然在某些情况下是有益的，例如在先天免疫系统中，但这种反应也会引起过敏反应，包括哮喘和过敏反应。肥大细胞的异常增殖是许多肥大细胞瘤的特征。触发肥大细胞脱颗粒的信号通路的细节需要进一步确定。SWAP-70蛋白是我们之前从B细胞中发现的一种新型信号转导蛋白，在肥大细胞中也有表达。我们最近生成的SWAP-70 -/-小鼠的肥大细胞显示fc - epsilonri触发的脱颗粒受损。这表明SWAP-70蛋白对肥大细胞生物学的重要贡献，即胞吐作用。具体来说，我们假设SWAP-70通过其新确定的rac特异性鸟苷核苷酸交换活性对肥大细胞中fc - epsilonri触发的胞外作用很重要。因此，我们旨在了解SWAP-70在导致fc - epsilonri触发胞外分泌的信号通路中的作用和地位，并探索SWAP-70本身是如何被调节的。为了实现这一目标，我们将应用生物化学和细胞方法的结合。所提出的实验应获得肥大细胞胞吐调节途径的关键信息，并将有助于理解肥大细胞相关疾病，如过敏反应。

DESCRIPTION (provided by applicant): Mast cells play diverse and important roles in the mammalian immune system. Upon aggregation of the Fc-epsilonRI receptor, mast cells can degranulate and release histamine and other biologically active compounds. While beneficial in some instances, e.g. within the innate immune system, such reactions are also causing allergic reactions, including asthma and anaphylaxis. Aberrant proliferation of mast cells characterizes many mast cell tumors. Details of the signaling pathways that trigger mast cell degranulation need to be further defined. Protein SWAP-70, identified by us earlier from B cells, has signatures of a novel type of signal transducing protein, and is also expressed in mast cells. Mast cells derived from our recently generated SWAP-70 -/- mice show impaired Fc-epsilonRI-triggered degranulation. This proposal suggests an important contribution of protein SWAP-70 to mast cell biology, i.e. exocytosis. Specifically, we hypothesize that SWAP-70 through its newly determined Rac-specific guanosine nucleotide exchange activity is important for Fc-epsilonRI-triggered exocytosis in mast cells. Therefore, we aim at understanding the role and position of SWAP- 70 in the signaling pathway leading to Fc-epsilonRI-triggered exocytosis, and will explore how SWAP-70 itself is regulated. Towards this goal, we will apply a combination of biochemical and cellular approaches. The proposed experiments should yield key information on pathways regulating mast cell exocytosis, and will help understanding mast cell-associated diseases such as allergic reactions.